Thalomid

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of
THALOMID is not fully understood. THALOMID possesses immunomodulatory,
antiinflammatory and antiangiogenic properties. Available data from in vitro studies
and clinical trials suggest that the immunologic effects of this compound can
vary substantially under different conditions, but may be related to
suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected cell
surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been
reported to decrease circulating levels of TNF-α
in patients with erythema nodosum leprosum (ENL); however, it has also been
shown to increase plasma TNF-α levels in HIV-seropositive patients.
Other anti-inflammatory and immunomodulatory
properties of thalidomide may include suppression of macrophage involvement in
prostaglandin synthesis, and modulation of interleukin-10 and interleukin-12
production by peripheral blood mononuclear cells. Thalidomide treatment of
multiple myeloma patients is accompanied by an increase in the number of
circulating natural killer cells, and an increase in plasma levels of
interleukin-2 and interferon-gamma (T cell-derived cytokines associated with
cytotoxic activity). Thalidomide was found to inhibit angiogenesis in a human
umbilical artery explant model in vitro. The cellular processes of angiogenesis
inhibited by thalidomide may include the proliferation of endothelial cells.

Pharmacokinetics

Absorption

Absorption of THALOMID is slow
after oral administration. The maximum plasma concentrations are reached
approximately 2-5 hours after administration. The absolute bioavailability of
thalidomide from thalidomide capsules has not yet been characterized in human
subjects due to its poor aqueous solubility. Based on the 14C-radiolabel
thalidomide study in human, greater than 90% of the total radioactivity is
recovered in urine suggesting good oral absorption. While the extent of
absorption (as measured by area under the curve [AUC]) is proportional to dose
in healthy subjects, the observed peak concentration (Cmax) increased in a less
than proportional manner (see Table 5 below). This lack of Cmax dose
proportionality, coupled with the observed increase in Tmax values, suggests
that the poor solubility of thalidomide in aqueous media may be hindering the
rate of absorption.

Table 5: Pharmacokinetic Parameter Values for THALOMID
Mean (%CV)

Population/ Single Dose

AUC0-∞ μg•hr/mL

Cmax μg/mL

Tmax (hrs)

Half-life (hrs)

Healthy Subjects (n=14)

50 mg

4.9 (16%)

0.62 (52%)

2.9 (66%)

5.52 (37%)

200 mg

18.9 (17%)

1.76 (30%)

3.5 (57%)

5.53 (25%)

400 mg

36.4 (26%)

2.82 (28%)

4.3 (37%)

7.29 (36%)

Patients with Hansen’s Disease (n=6)

400 mg

46.4 (44.1%)

3.44 (52.6%)

5.7 (27%)

6.86 (17%)

Coadministration of THALOMID® (thalidomide) with a high-fat meal causes minor ( < 10%) changes in the
observed AUC and Cmax values; however, it causes an increase in Tmax to
approximately 6 hours.

Distribution

In human plasma, the geometric
mean plasma protein binding was 55% and 66%, respectively, for (+)-(R)- and
(-)-(S)-thalidomide. In a pharmacokinetic study of thalidomide in
HIV-seropositive adult male subjects receiving thalidomide 100 mg/day, thalidomide
was detectable in the semen.

Metabolism

In a 14C-radiolabel
ADME study in humans, unchanged drug is the predominant circulating component.
Thalidomide is not a substrate of the cytochrome P450 system. At therapeutic
concentrations, thalidomide is not an inhibitor or inducer of human cytochrome
P450 enzymes in vitro. Pharmacokinetic drug-drug interactions with substrates,
inhibitors or inducers of CYP450 are not anticipated.

Elimination

The mean elimination half-life
of thalidomide in plasma following single oral doses between 50 mg and 400 mg
was 5.5 to 7.3 hours. Following a single 400 mg oral dose of radiolabeled thalidomide,
the total mean recovery was 93.6% of the administered dose by Day 8. The
majority of the radioactive dose was excreted within 48 hours following dose
administration. In humans, 14C-thalidomide is primarily excreted in
urine (91.9% of the radioactive dose) mainly as hydrolytic metabolites while
fecal excretion is minor ( < 2% of the dose). Unchanged thalidomide is not
eliminated by the kidney to a notable degree ( < 3.5% of the dose).

Effects of Weight

There is a linear relationship
between body weight and estimated thalidomide clearance. In MM patients with
body weight from 47-133 kg, thalidomide clearance ranged from approximately
6-12 L/h, representing an increase in thalidomide clearance of 0.605 L/h per 10
kg body weight increase.

Effects of Age, Gender and Race

Analysis of the data from
pharmacokinetic studies in healthy volunteers and patients with Hansen's
disease ranging in age from 20 to 69 years does not reveal any age-related
changes.

While a comparative trial of
the effects of gender on thalidomide pharmacokinetics has not been conducted,
examination of the data for thalidomide does not reveal any significant gender
differences in pharmacokinetic parameter values.

Pharmacokinetic differences due
to race have not been studied.

Pharmacokinetic Data in Special
Populations

HIV-seropositive Subjects: There is no apparent
significant difference in measured pharmacokinetic parameter values between
healthy human subjects and HIV-seropositive subjects following single-dose
administration of THALOMID Capsules.

Patients with Hansen's
Disease: Analysis
of data from a small study in Hansen's patients suggests that these patients,
relative to healthy subjects, may have an increased bioavailability of
THALOMID. The increase is reflected both in an increased area under the curve
and in increased peak plasma levels. The clinical significance of this increase
is unknown.

Pediatric: No pharmacokinetic data
are available in subjects below the age of 18 years.

Clinical Studies

Multiple Myeloma (MM)

The efficacy and safety of THALOMID in patients with
multiple myeloma were evaluated in two randomized, multi-center studies (Study
1 and Study 2). Study 1 was an open-label study which randomized 207
symptomatic patients with newly diagnosed MM to THALOMID plus dexamethasone (N
= 103) versus dexamethasone alone (N=104). The THALOMID dose was 200 mg daily
and the dexamethasone dose was 40 mg orally once daily on days 1-4, 9-12, and
17-20 every 28-days. Each group was treated for four 28-day cycles.

Study 2 randomized 470 newly diagnosed patients with MM
to THALOMID plus dexamethasone (N=235) versus placebo plus dexamethasone (N=235).
In the THALOMID/dexamethasone arm, a starting dose of thalidomide 50 mg was
escalated to 200 mg/day (cycle 2) once daily for 28 days. Patients in both
treatment groups took 40 mg of dexamethasone once daily given on days 1-4,
9-12, and 17-20 (every 28 days). Beginning with Cycle 5, the dose of
dexamethasone was reduced to 40 mg once daily on Days 1 to 4 of each cycle.
Treatment continued as tolerated until disease progression.

Baseline demographics for both studies are presented in
Table 6 and disease characteristics for the study population are summarized in
Tables 7 (Study 1) and 8 (Study 2).

In Study 1, response rate was the primary endpoint.
Response rates based on serum or urine paraprotein measurements were
significantly higher in the combination arm (52% vs. 36%). The primary efficacy
endpoint in Study 2 was time to progression (TTP), defined as the time from
randomization to the first documentation of disease progression, based on the
myeloma response criteria. A preplanned interim analysis for Study 2
demonstrated that the combination of THALOMID plus dexamethasone was superior
to placebo plus dexamethasone with respect to TTP (Table 9).

Table 9: Summary of Efficacy (Study 2)

Thalidomide/ Dexamethasone
(N=235)

Placebo/ Dexamethasone
(N=235)

Time to Progression

Progressed - n (%)

72 (31)

126 (54)

Median(Weeks) (95% CIa)

97.7 (61.86, NR)

28.3 (27.71, 36.43)

Hazard Ratio (95% CI)b

0.43 (0.32, 0.58)

P-valuec

< 0.0001

Overall Survival

Death - n(%)

57 (24)

68 (29)

Median (Weeks) (95% CIa)

NR (112.14, NR)

128.6 (113.43, NR)

Hazard Ratio (95% CI)b

0.82 (0.57, 1.16)

Myeloma Response Rated - n (%)

Complete Response (CR)

18 (8)

6 (3)

Partial Response (PR)

130 (55)

102 (43)

Overall Response (CR + PR)

148 (63)

108 (46)

95% CI(%)

(56, 69)

(39, 53)

aThe 95% confidence intervals about the median overall TTP,
or median overall survival. CI: confidence interval; NR: not reached. bBased on a proportional hazards model comparing the hazard
functions associated with treatment groups thalidomide/dexamethasone:placebo/dexamethasone). cP-value based on the interim analysis was compared with the nominal
significance level of 0.0027. Based on a one-sided unstratified log rank test
of survival curve differences between treatment groups.dDisease response assessments were determined according to the Bladé
criteria. Response is the highest assessment of response during the treatment
phase of the study.

The Kaplan-Meier plot of the
time to progression by treatment group is presented in Figure 1.

Erythema Nodosum Leprosum (ENL)

The primary data demonstrating
the efficacy of thalidomide in the treatment of the cutaneous manifestations of
moderate to severe ENL are derived from the published medical literature and
from a retrospective study of 102 patients treated by the U.S. Public Health
Service.

Two double-blind, randomized,
controlled trials reported the dermatologic response to a 7-day course of 100
mg thalidomide (four times daily) or control. Dosage was lower for patients
under 50 kg in weight.

Waters reported the results of
two studies, both double-blind, randomized, placebo-controlled, crossover
trials in a total of 10 hospitalized, steroid-dependent patients with chronic
ENL treated with 100 mg thalidomide or placebo (three times daily). All
patients also received dapsone. The primary endpoint was reduction in weekly
steroid dosage.

Data on the efficacy of thalidomide in prevention of ENL relapse were derived from a retrospective
evaluation of 102 patients treated under the auspices of the U.S. Public Health
Service. A subset of patients with ENL controlled on thalidomide demonstrated
repeated relapse upon drug withdrawal and remission with reinstitution of
therapy.

Twenty U.S. patients between
the ages of 11 and 17 years were treated with thalidomide, generally at 100 mg
daily. Response rates and safety profiles were similar to that observed in the
adult population.

Thirty-two other published
studies containing over 1600 patients consistently report generally successful
treatment of the cutaneous manifestations of moderate to severe ENL with
thalidomide.

Last reviewed on RxList: 7/7/2014
This monograph has been modified to include the generic and brand name in many instances.